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1.
J Neuroinflammation ; 21(1): 145, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824526

ABSTRACT

BACKGROUND: Recent experimental studies of neuroinflammation in glaucoma pointed to cFLIP as a molecular switch for cell fate decisions, mainly regulating cell type-specific caspase-8 functions in cell death and inflammation. This study aimed to determine the importance of cFLIP for regulating astroglia-driven neuroinflammation in experimental glaucoma by analyzing the outcomes of astroglia-targeted transgenic deletion of cFLIP or cFLIPL. METHODS: Glaucoma was modeled by anterior chamber microbead injections to induce ocular hypertension in mouse lines with or without conditional deletion of cFLIP or cFLIPL in astroglia. Morphological analysis of astroglia responses assessed quantitative parameters in retinal whole mounts immunolabeled for GFAP and inflammatory molecules or assayed for TUNEL. The molecular analysis included 36-plexed immunoassays of the retina and optic nerve cytokines and chemokines, NanoString-based profiling of inflammation-related gene expression, and Western blot analysis of selected proteins in freshly isolated samples of astroglia. RESULTS: Immunoassays and immunolabeling of retina and optic nerve tissues presented reduced production of various proinflammatory cytokines, including TNFα, in GFAP/cFLIP and GFAP/cFLIPL relative to controls at 12 weeks of ocular hypertension with no detectable alteration in TUNEL. Besides presenting a similar trend of the proinflammatory versus anti-inflammatory molecules displayed by immunoassays, NanoString-based molecular profiling detected downregulated NF-κB/RelA and upregulated RelB expression of astroglia in ocular hypertensive samples of GFAP/cFLIP compared to ocular hypertensive controls. Analysis of protein expression also revealed decreased phospho-RelA and increased phospho-RelB in parallel with an increase in caspase-8 cleavage products. CONCLUSIONS: A prominent response limiting neuroinflammation in ocular hypertensive eyes with cFLIP-deletion in astroglia values the role of cFLIP in the molecular regulation of glia-driven neuroinflammation during glaucomatous neurodegeneration. The molecular responses accompanying the lessening of neurodegenerative inflammation also seem to maintain astroglia survival despite increased caspase-8 cleavage with cFLIP deletion. A transcriptional autoregulatory response, dampening RelA but boosting RelB for selective expression of NF-κB target genes, might reinforce cell survival in cFLIP-deleted astroglia.


Subject(s)
Astrocytes , CASP8 and FADD-Like Apoptosis Regulating Protein , Glaucoma , Neuroinflammatory Diseases , Animals , CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism , CASP8 and FADD-Like Apoptosis Regulating Protein/genetics , Mice , Astrocytes/metabolism , Astrocytes/pathology , Glaucoma/metabolism , Glaucoma/pathology , Glaucoma/genetics , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/pathology , Mice, Transgenic , Disease Models, Animal , Cytokines/metabolism , Retina/metabolism , Retina/pathology , Mice, Inbred C57BL , Optic Nerve/pathology , Optic Nerve/metabolism , Glial Fibrillary Acidic Protein/metabolism
2.
Eur J Med Res ; 29(1): 321, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38858735

ABSTRACT

BACKGROUND: Migraine, as a prevalent neurologic disorder, involves intricate and yet incompletely elucidated pathophysiological mechanisms. A plethora of research findings underscores the pivotal role played by astrocytes in the progression of migraines. In order to elucidate the current advances and directions in research pertaining to astrocytes in migraines, we conducted bibliometric analysis of relevant literature and visualized the results. Subsequently, we expound upon these findings to contribute to the evolving understanding of the role of astrocytes in migraine pathophysiology. METHODS: On November 21, 2023, we conducted a search on Web of Science (WOS), restricting the document type to articles or reviews and language to English. Following a meticulous selection process involving three researchers, we identified the literature to be included in our analysis. Subsequently, we employed Microsoft Office Excel programs, R, VOSviewer, Scimago Graphica, and CiteSpace software to conduct visualization analysis of basic information and trends regarding journals, countries/regions, and influential authors, institutions, keywords, and papers. RESULTS: As of November 21, 2023, relevant literature has been published in 71 journals across 27 countries/regions. This corpus comprises contributions from 576 authors affiliated with 220 institutions, encompassing 865 keywords and referencing 6065 scholarly articles. CEPHALALGIA stands out as the most influential journal in this field, while authors PIETROBON D and DALKARA T have significant impact. The United States is highly influential, with CNR and UNIV PADUA emerging as highly influential institutions. The predominant category is Neurosciences. CONCLUSIONS: Future investigators may continue to focus on migraines with aura, familial hemiplegic migraine (FHM), and the crucial calcitonin gene-related peptide (CGRP) system. Employing advanced observational techniques, such as imaging, researchers should pay attention to cellular and tissue structures, such as microglia and the trigeminal ganglion, as well as mechanisms involving inflammation and central sensitization. Moreover, animal models are paramount in obtaining high-quality evidence.


Subject(s)
Astrocytes , Bibliometrics , Migraine Disorders , Humans , Astrocytes/pathology
3.
Cells ; 13(9)2024 May 04.
Article in English | MEDLINE | ID: mdl-38727321

ABSTRACT

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deficiency of the survival motor neuron (SMN) protein. Although SMA is a genetic disease, environmental factors contribute to disease progression. Common pathogen components such as lipopolysaccharides (LPS) are considered significant contributors to inflammation and have been associated with muscle atrophy, which is considered a hallmark of SMA. In this study, we used the SMNΔ7 experimental mouse model of SMA to scrutinize the effect of systemic LPS administration, a strong pro-inflammatory stimulus, on disease outcome. Systemic LPS administration promoted a reduction in SMN expression levels in CNS, peripheral lymphoid organs, and skeletal muscles. Moreover, peripheral tissues were more vulnerable to LPS-induced damage compared to CNS tissues. Furthermore, systemic LPS administration resulted in a profound increase in microglia and astrocytes with reactive phenotypes in the CNS of SMNΔ7 mice. In conclusion, we hereby show for the first time that systemic LPS administration, although it may not precipitate alterations in terms of deficits of motor functions in a mouse model of SMA, it may, however, lead to a reduction in the SMN protein expression levels in the skeletal muscles and the CNS, thus promoting synapse damage and glial cells' reactive phenotype.


Subject(s)
Disease Models, Animal , Lipopolysaccharides , Muscular Atrophy, Spinal , Animals , Lipopolysaccharides/pharmacology , Muscular Atrophy, Spinal/pathology , Muscular Atrophy, Spinal/metabolism , Mice , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Muscle, Skeletal/metabolism , Microglia/metabolism , Microglia/drug effects , Microglia/pathology , Survival of Motor Neuron 1 Protein/metabolism , Survival of Motor Neuron 1 Protein/genetics , Mice, Inbred C57BL , Astrocytes/metabolism , Astrocytes/drug effects , Astrocytes/pathology , Inflammation/pathology
4.
Sci Rep ; 14(1): 10433, 2024 05 07.
Article in English | MEDLINE | ID: mdl-38714696

ABSTRACT

Toxoplasma gondii (T. gondii) is a protozoan parasite that infects approximately one-third of the global human population, often leading to chronic infection. While acute T. gondii infection can cause neural damage in the central nervous system and result in toxoplasmic encephalitis, the consequences of T. gondii chronic infection (TCI) are generally asymptomatic. However, emerging evidence suggests that TCI may be linked to behavioral changes or mental disorders in hosts. Astrocyte polarization, particularly the A1 subtype associated with neuronal apoptosis, has been identified in various neurodegenerative diseases. Nevertheless, the role of astrocyte polarization in TCI still needs to be better understood. This study aimed to establish a mouse model of chronic TCI and examine the transcription and expression levels of glial fibrillary acidic protein (GFAP), C3, C1q, IL-1α, and TNF-α in the brain tissues of the mice. Quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay, and Western blotting were employed to assess these levels. Additionally, the expression level of the A1 astrocyte-specific marker C3 was evaluated using indirect fluorescent assay (IFA). In mice with TCI, the transcriptional and expression levels of the inflammatory factors C1q, IL-1α, and TNF-α followed an up-down-up pattern, although they remained elevated compared to the control group. These findings suggest a potential association between astrocyte polarization towards the A1 subtype and synchronized changes in these three inflammatory mediators. Furthermore, immunofluorescence assay (IFA) revealed a significant increase in the A1 astrocytes (GFAP+C3+) proportion in TCI mice. This study provides evidence that TCI can induce astrocyte polarization, a biological process that may be influenced by changes in the levels of three inflammatory factors: C1q, IL-1α, and TNF-α. Additionally, the release of neurotoxic substances by A1 astrocytes may be associated with the development of TCI.


Subject(s)
Astrocytes , Brain , Toxoplasma , Animals , Astrocytes/metabolism , Astrocytes/parasitology , Astrocytes/pathology , Mice , Toxoplasma/pathogenicity , Toxoplasma/physiology , Brain/parasitology , Brain/metabolism , Brain/pathology , Disease Models, Animal , Female , Chronic Disease , Cell Polarity , Glial Fibrillary Acidic Protein/metabolism , Glial Fibrillary Acidic Protein/genetics , Toxoplasmosis/metabolism , Toxoplasmosis/parasitology , Toxoplasmosis/pathology , Tumor Necrosis Factor-alpha/metabolism , Toxoplasmosis, Cerebral/parasitology , Toxoplasmosis, Cerebral/pathology , Toxoplasmosis, Cerebral/metabolism
5.
Sci Rep ; 14(1): 10877, 2024 05 13.
Article in English | MEDLINE | ID: mdl-38740862

ABSTRACT

In chronic stages of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalitis (EAE), connexin (Cx)43 gap junction channel proteins are overexpressed because of astrogliosis. To elucidate the role of increased Cx43, the central nervous system (CNS)-permeable Cx blocker INI-0602 was therapeutically administered. C57BL6 mice with chronic EAE initiated by MOG35-55 received INI-0602 (40 mg/kg) or saline intraperitoneally every other day from days post-immunization (dpi) 17-50. Primary astroglia were employed to observe calcein efflux responses. In INI-0602-treated mice, EAE clinical signs improved significantly in the chronic phase, with reduced demyelination and decreased CD3+ T cells, Iba-1+ and F4/80+ microglia/macrophages, and C3+GFAP+ reactive astroglia infiltration in spinal cord lesions. Flow cytometry analysis of CD4+ T cells from CNS tissues revealed significantly reduced Th17 and Th17/Th1 cells (dpi 24) and Th1 cells (dpi 50). Multiplex array of cerebrospinal fluid showed significantly suppressed IL-6 and significantly increased IL-10 on dpi 24 in INI-0602-treated mice, and significantly suppressed IFN-γ and MCP-1 on dpi 50 in the same group. In vitro INI-0602 treatment inhibited ATP-induced calcium propagations of Cx43+/+ astroglial cells to similar levels of those of Cx43-/- cells. Astroglial Cx43 hemichannels represent a novel therapeutic target for chronic EAE and MS.


Subject(s)
Astrocytes , Connexin 43 , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental , Mice, Inbred C57BL , Multiple Sclerosis , Animals , Connexin 43/metabolism , Astrocytes/metabolism , Astrocytes/drug effects , Astrocytes/pathology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Mice , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Female
6.
Cell Rep ; 43(5): 114193, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38709635

ABSTRACT

Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests that ion homeostasis is a cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates BBB disruption, which was rescued by pharmacological or genetic inhibition of the CCL2-CCR2 pathway in vivo. Together, our study identifies the astrocytic Slc4a4-CCL2 and endothelial CCR2 axis as a mechanism controlling BBB integrity and repair, while providing insights for a therapeutic approach against BBB-related CNS disorders.


Subject(s)
Astrocytes , Blood-Brain Barrier , Chemokine CCL2 , Receptors, CCR2 , Stroke , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Astrocytes/metabolism , Astrocytes/pathology , Receptors, CCR2/metabolism , Animals , Chemokine CCL2/metabolism , Stroke/metabolism , Stroke/pathology , Mice , Signal Transduction , Male , Humans , Mice, Inbred C57BL , Brain/metabolism , Brain/pathology
7.
Acta Neuropathol ; 147(1): 84, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38750212

ABSTRACT

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.


Subject(s)
Amyotrophic Lateral Sclerosis , Astrocytes , DNA-Binding Proteins , Mitochondrial Proteins , Transcription Factors , Astrocytes/pathology , Astrocytes/metabolism , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Humans , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Mitochondria/pathology , Mitochondria/metabolism , Male , Female , Middle Aged , Aged
8.
Acta Neuropathol ; 147(1): 92, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38801558

ABSTRACT

The SARS-CoV-2 virus that led to COVID-19 is associated with significant and long-lasting neurologic symptoms in many patients, with an increased mortality risk for people with Alzheimer's disease (AD) and/or Down syndrome (DS). However, few studies have evaluated the neuropathological and inflammatory sequelae in postmortem brain tissue obtained from AD and people with DS with severe SARS-CoV-2 infections. We examined tau, beta-amyloid (Aß), inflammatory markers and SARS-CoV-2 nucleoprotein in DS, AD, and healthy non-demented controls with COVID-19 and compared with non-infected brain tissue from each disease group (total n = 24). A nested ANOVA was used to determine regional effects of the COVID-19 infection on arborization of astrocytes (Sholl analysis) and percent-stained area of Iba-1 and TMEM 119. SARS-CoV-2 antibodies labeled neurons and glial cells in the frontal cortex of all subjects with COVID-19, and in the hippocampus of two of the three DS COVID-19 cases. SARS-CoV-2-related alterations were observed in peri-vascular astrocytes and microglial cells in the gray matter of the frontal cortex, hippocampus, and para-hippocampal gyrus. Bright field microscopy revealed scattered intracellular and diffuse extracellular Aß deposits in the hippocampus of controls with confirmed SARS-CoV-2 infections. Overall, the present preliminary findings suggest that SARS-CoV-2 infections induce abnormal inflammatory responses in Down syndrome.


Subject(s)
Alzheimer Disease , Brain , COVID-19 , Down Syndrome , Humans , Down Syndrome/pathology , Down Syndrome/metabolism , Down Syndrome/complications , Alzheimer Disease/pathology , Alzheimer Disease/virology , Alzheimer Disease/metabolism , COVID-19/pathology , COVID-19/complications , Male , Female , Aged , Middle Aged , Brain/pathology , Brain/virology , Aged, 80 and over , Astrocytes/pathology , Astrocytes/virology , Astrocytes/metabolism , Amyloid beta-Peptides/metabolism , SARS-CoV-2/pathogenicity , Microglia/pathology , Microglia/metabolism , Adult , tau Proteins/metabolism
9.
Cells ; 13(10)2024 May 14.
Article in English | MEDLINE | ID: mdl-38786054

ABSTRACT

Prion diseases are rare and neurodegenerative diseases that are characterized by the misfolding and infectious spread of the prion protein in the brain, causing progressive and irreversible neuronal loss and associated clinical and behavioral manifestations in humans and animals, ultimately leading to death. The brain has a complex network of neurons and glial cells whose crosstalk is critical for function and homeostasis. Although it is established that prion infection of neurons is necessary for clinical disease to occur, debate remains in the field as to the role played by glial cells, namely astrocytes and microglia, and whether these cells are beneficial to the host or further accelerate disease. Here, we review the current literature assessing the complex morphologies of astrocytes and microglia, and the crosstalk between these two cell types, in the prion-infected brain.


Subject(s)
Neuroglia , Prion Diseases , Humans , Prion Diseases/pathology , Prion Diseases/metabolism , Animals , Neuroglia/pathology , Neuroglia/metabolism , Astrocytes/pathology , Astrocytes/metabolism , Brain/pathology , Brain/metabolism , Neurobiology , Microglia/pathology , Microglia/metabolism , Neurons/metabolism , Neurons/pathology , Neuropathology , Prions/metabolism
10.
Cell Death Dis ; 15(5): 361, 2024 May 25.
Article in English | MEDLINE | ID: mdl-38796462

ABSTRACT

Disease models of neurodegeneration with brain iron accumulation (NBIA) offer the possibility to explore the relationship between iron dyshomeostasis and neurodegeneration. We analyzed hiPS-derived astrocytes from PANK2-associated neurodegeneration (PKAN), an NBIA disease characterized by progressive neurodegeneration and high iron accumulation in the globus pallidus. Previous data indicated that PKAN astrocytes exhibit alterations in iron metabolism, general impairment of constitutive endosomal trafficking, mitochondrial dysfunction and acquired neurotoxic features. Here, we performed a more in-depth analysis of the interactions between endocytic vesicles and mitochondria via superresolution microscopy experiments. A significantly lower number of transferrin-enriched vesicles were in contact with mitochondria in PKAN cells than in control cells, confirming the impaired intracellular fate of cargo endosomes. The investigation of cytosolic and mitochondrial iron parameters indicated that mitochondrial iron availability was substantially lower in PKAN cells compared to that in the controls. In addition, PKAN astrocytes exhibited defects in tubulin acetylation/phosphorylation, which might be responsible for unregulated vesicular dynamics and inappropriate iron delivery to mitochondria. Thus, the impairment of iron incorporation into these organelles seems to be the cause of cell iron delocalization, resulting in cytosolic iron overload and mitochondrial iron deficiency, triggering mitochondrial dysfunction. Overall, the data elucidate the mechanism of iron accumulation in CoA deficiency, highlighting the importance of mitochondrial iron deficiency in the pathogenesis of disease.


Subject(s)
Astrocytes , Cytosol , Iron Overload , Iron , Mitochondria , Astrocytes/metabolism , Astrocytes/pathology , Humans , Mitochondria/metabolism , Cytosol/metabolism , Iron/metabolism , Iron Overload/metabolism , Iron Overload/pathology , Tubulin/metabolism , Phosphorylation , Iron Deficiencies , Acetylation
11.
J Neuroinflammation ; 21(1): 137, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38802820

ABSTRACT

Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. The increased astrocyte proliferation by hyperglycemia was reduced by Glut1 inhibitor BAY-876. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreERT2;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, and proinflammatory phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. In line with findings from mouse experiments, a high-glucose environment intensified the LPS-triggered production of proinflammatory molecules in primary astrocyte cultures. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.


Subject(s)
Astrocytes , Brain , Hyperglycemia , Lipopolysaccharides , Mice, Inbred C57BL , Neuroinflammatory Diseases , Animals , Hyperglycemia/chemically induced , Hyperglycemia/pathology , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Mice , Lipopolysaccharides/toxicity , Lipopolysaccharides/pharmacology , Brain/pathology , Brain/metabolism , Brain/drug effects , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/pathology , Neuroinflammatory Diseases/chemically induced , Male , Cellular Reprogramming/drug effects , Cellular Reprogramming/physiology , Mice, Transgenic , Cells, Cultured
12.
Biomolecules ; 14(5)2024 May 10.
Article in English | MEDLINE | ID: mdl-38785974

ABSTRACT

Diabetic retinopathy (DR) affects over 140 million people globally. The mechanisms that lead to blindness are still enigmatic but there is evidence that sustained inflammation and hypoxia contribute to vascular damage. Despite efforts to understand the role of inflammation and microglia in DR's pathology, the contribution of astrocytes to hypoxic responses is less clear. To investigate the role of astrocytes in hypoxia-induced retinopathy, we utilized a 7-day systemic hypoxia model using the GFAP-CreERT2:Rosa26iDTR transgenic mouse line. This allows for the induction of inflammatory reactive astrogliosis following tamoxifen and diphtheria toxin administration. We hypothesize that DTx-induced astrogliosis is neuroprotective during hypoxia-induced retinopathy. Glial, neuronal, and vascular responses were quantified using immunostaining, with antibodies against GFAP, vimentin, IBA-1, NeuN, fibrinogen, and CD31. Cytokine responses were measured in both the brain and serum. We report that while both DTx and hypoxia induced a phenotype of reduced microglia morphological activation, DTx, but not hypoxia, induced an increase in the Müller glia marker vimentin. We did not observe that the combination of DTx and hypoxic treatments exacerbated the signs of reactive glial cells, nor did we observe a significant change in the expression immunomodulatory mediators IL-1ß, IL2, IL-4, IL-5, IL-6, IL-10, IL-18, CCL17, TGF-ß1, GM-CSF, TNF-α, and IFN-γ. Overall, our results suggest that, in this hypoxia model, reactive astrogliosis does not alter the inflammatory responses or cause vascular damage in the retina.


Subject(s)
Disease Models, Animal , Ependymoglial Cells , Gliosis , Mice, Transgenic , Microglia , Animals , Gliosis/pathology , Gliosis/metabolism , Gliosis/chemically induced , Mice , Microglia/metabolism , Microglia/pathology , Microglia/drug effects , Ependymoglial Cells/metabolism , Ependymoglial Cells/pathology , Ependymoglial Cells/drug effects , Retina/metabolism , Retina/pathology , Retina/drug effects , Hypoxia/metabolism , Hypoxia/pathology , Astrocytes/metabolism , Astrocytes/pathology , Astrocytes/drug effects , Glial Fibrillary Acidic Protein/metabolism , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/pathology , Cytokines/metabolism , Vimentin/metabolism , Vimentin/genetics , Diphtheria Toxin
13.
Cells ; 13(10)2024 May 14.
Article in English | MEDLINE | ID: mdl-38786059

ABSTRACT

In recent decades, there has been a dramatic rise in the rates of children being born after in utero exposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a powerful influence on synaptic development, secreting factors to either promote or inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist buprenorphine on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on the excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, indicating a complex neuroadaptive response in the event of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LDs), suggestive of a maladaptive stress response in the developing CNS.


Subject(s)
Analgesics, Opioid , Astrocytes , Neurons , Prenatal Exposure Delayed Effects , Signal Transduction , Synapses , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Animals , Synapses/metabolism , Synapses/drug effects , Female , Pregnancy , Mice , Analgesics, Opioid/pharmacology , Analgesics, Opioid/adverse effects , Prenatal Exposure Delayed Effects/pathology , Prenatal Exposure Delayed Effects/metabolism , Neurons/metabolism , Neurons/drug effects , Neurons/pathology , Signal Transduction/drug effects , Buprenorphine/pharmacology , Cells, Cultured , Mice, Inbred C57BL
14.
J Neuroinflammation ; 21(1): 130, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38750510

ABSTRACT

Epidemiological studies have unveiled a robust link between exposure to repetitive mild traumatic brain injury (r-mTBI) and elevated susceptibility to develop neurodegenerative disorders, notably chronic traumatic encephalopathy (CTE). The pathogenic lesion in CTE cases is characterized by the accumulation of hyperphosphorylated tau in neurons around small cerebral blood vessels which can be accompanied by astrocytes that contain phosphorylated tau, the latter termed tau astrogliopathy. However, the contribution of tau astrogliopathy to the pathobiology and functional consequences of r-mTBI/CTE or whether it is merely a consequence of aging remains unclear. We addressed these pivotal questions by utilizing a mouse model harboring tau-bearing astrocytes, GFAPP301L mice, subjected to our r-mTBI paradigm. Despite the fact that r-mTBI did not exacerbate tau astrogliopathy or general tauopathy, it increased phosphorylated tau in the area underneath the impact site. Additionally, gene ontology analysis of tau-bearing astrocytes following r-mTBI revealed profound alterations in key biological processes including immunological and mitochondrial bioenergetics. Moreover, gene array analysis of microdissected astrocytes accrued from stage IV CTE human brains revealed an immunosuppressed astroglial phenotype similar to tau-bearing astrocytes in the GFAPP301L model. Additionally, hippocampal reduction of proteins involved in water transport (AQP4) and glutamate homeostasis (GLT1) was found in the mouse model of tau astrogliopathy. Collectively, these findings reveal the importance of understanding tau astrogliopathy and its role in astroglial pathobiology under normal circumstances and following r-mTBI. The identified mechanisms using this GFAPP301L model may suggest targets for therapeutic interventions in r-mTBI pathogenesis in the context of CTE.


Subject(s)
Aquaporin 4 , Astrocytes , Excitatory Amino Acid Transporter 2 , Mice, Transgenic , Tauopathies , tau Proteins , Astrocytes/metabolism , Astrocytes/pathology , Animals , Mice , tau Proteins/metabolism , tau Proteins/genetics , Aquaporin 4/metabolism , Aquaporin 4/genetics , Tauopathies/metabolism , Tauopathies/pathology , Tauopathies/genetics , Humans , Excitatory Amino Acid Transporter 2/metabolism , Excitatory Amino Acid Transporter 2/genetics , Excitatory Amino Acid Transporter 2/biosynthesis , Brain Concussion/metabolism , Brain Concussion/pathology , Male , Phenotype , Mice, Inbred C57BL
15.
Front Endocrinol (Lausanne) ; 15: 1393253, 2024.
Article in English | MEDLINE | ID: mdl-38800473

ABSTRACT

Metabolic syndrome (MetS) and cognitive dysfunction pose significant challenges to global health and the economy. Systemic inflammation, endocrine disruption, and autoregulatory impairment drive neurodegeneration and microcirculatory damage in MetS. Due to their unique anatomy and function, astrocytes sense and integrate multiple metabolic signals, including peripheral endocrine hormones and nutrients. Astrocytes and synapses engage in a complex dialogue of energetic and immunological interactions. Astrocytes act as a bridge between MetS and cognitive dysfunction, undergoing diverse activation in response to metabolic dysfunction. This article summarizes the alterations in astrocyte phenotypic characteristics across multiple pathological factors in MetS. It also discusses the clinical value of astrocytes as a critical pathologic diagnostic marker and potential therapeutic target for MetS-associated cognitive dysfunction.


Subject(s)
Astrocytes , Cognitive Dysfunction , Metabolic Syndrome , Humans , Astrocytes/metabolism , Astrocytes/pathology , Metabolic Syndrome/metabolism , Metabolic Syndrome/physiopathology , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/etiology , Cognitive Dysfunction/physiopathology , Animals
16.
Nat Commun ; 15(1): 4549, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811525

ABSTRACT

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.


Subject(s)
Astrocytes , Brain Neoplasms , Breast Neoplasms , MicroRNAs , Neurons , Humans , MicroRNAs/metabolism , MicroRNAs/genetics , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Brain Neoplasms/secondary , Brain Neoplasms/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Female , Animals , Cell Line, Tumor , Astrocytes/metabolism , Astrocytes/pathology , Neurons/metabolism , Neurons/pathology , Mice , Excitatory Amino Acid Transporter 2/metabolism , Excitatory Amino Acid Transporter 2/genetics , Extracellular Vesicles/metabolism , Monocarboxylic Acid Transporters/metabolism , Monocarboxylic Acid Transporters/genetics , Gene Expression Regulation, Neoplastic , Glutamic Acid/metabolism , Glutamine/metabolism , Brain/metabolism , Brain/pathology , Lactic Acid/metabolism , Cell Proliferation
17.
Proc Natl Acad Sci U S A ; 121(22): e2315690121, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38781206

ABSTRACT

The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimer's disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, and the potential for coupling between the entry and nucleation mechanisms has been little explored. We found that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes. This in turn leads to lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin-3, to the lysosomal membrane. These observations are consistent with nanoscale damage of the lysosomal membrane. Live cell imaging and STORM superresolution microscopy further show that the nucleation of cytosolic tau occurs primarily at the lysosome membrane under these conditions. These data suggest that tau seeds escape from lysosomes via nanoscale damage rather than wholesale rupture and that nucleation of cytosolic tau commences as soon as tau fibril ends emerge from the lysosomal membrane.


Subject(s)
Cytosol , Lysosomes , tau Proteins , tau Proteins/metabolism , Lysosomes/metabolism , Cytosol/metabolism , Animals , Astrocytes/metabolism , Astrocytes/pathology , Neurons/metabolism , Neurons/pathology , Humans , Intracellular Membranes/metabolism , Endocytosis , Mice , Cells, Cultured
18.
Cell Rep Med ; 5(5): 101570, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38749422

ABSTRACT

While an association between Parkinson's disease (PD) and viral infections has been recognized, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on PD progression remains unclear. Here, we demonstrate that SARS-CoV-2 infection heightens the risk of PD using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons and a human angiotensin-converting enzyme 2 (hACE2) transgenic (Tg) mouse model. Our findings reveal that SARS-CoV-2 infection exacerbates PD susceptibility and cellular toxicity in DA neurons pre-treated with human preformed fibrils (hPFFs). Additionally, nasally delivered SARS-CoV-2 infects DA neurons in hACE2 Tg mice, aggravating the damage initiated by hPFFs. Mice infected with SARS-CoV-2 display persisting neuroinflammation even after the virus is no longer detectable in the brain. A comprehensive analysis suggests that the inflammatory response mediated by astrocytes and microglia could contribute to increased PD susceptibility associated with SARS-CoV-2. These findings advance our understanding of the potential long-term effects of SARS-CoV-2 infection on the progression of PD.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Disease Models, Animal , Dopaminergic Neurons , Mice, Transgenic , Parkinson Disease , SARS-CoV-2 , Animals , Dopaminergic Neurons/pathology , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/virology , Humans , COVID-19/pathology , COVID-19/virology , Parkinson Disease/pathology , Parkinson Disease/virology , Mice , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Microglia/pathology , Microglia/metabolism , Microglia/virology , Human Embryonic Stem Cells/metabolism , Astrocytes/pathology , Astrocytes/virology , Astrocytes/metabolism , Brain/pathology , Brain/virology
19.
BMJ Case Rep ; 17(5)2024 May 09.
Article in English | MEDLINE | ID: mdl-38724215

ABSTRACT

Autoimmune encephalitis due to glial fibrillar acidic protein (GFAP) astrocytopathy is a rare cause of subacute neuropsychiatric changes. In this case, a young patient presented with a viral prodrome and meningismus, followed by progressive encephalopathy and movement disorders over the span of 2 weeks. Due to his clinical trajectory, inflammatory cerebrospinal fluid (CSF) analysis, initial normal brain imaging and negative serum autoimmune encephalopathy panel, his initial diagnosis was presumed viral meningoencephalitis. The recurrence and progression of neuropsychiatric symptoms and myoclonus despite antiviral treatment prompted further investigation, inclusive of testing for CSF autoimmune encephalopathy autoantibodies, yielding a clinically meaningful, positive GFAP autoantibody. This case highlights the importance of appropriately testing both serum and CSF autoantibodies when an autoimmune encephalitic process is considered. Through this case, we review the clinical and radiographic manifestations of GFAP astrocytopathy, alongside notable pearls pertaining to this autoantibody syndrome and its management.


Subject(s)
Autoimmune Diseases of the Nervous System , Encephalitis , Glial Fibrillary Acidic Protein , Adult , Humans , Male , Astrocytes/pathology , Astrocytes/immunology , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Autoimmune Diseases of the Nervous System/diagnosis , Autoimmune Diseases of the Nervous System/immunology , Diagnosis, Differential , Encephalitis/diagnosis , Encephalitis/immunology , Glial Fibrillary Acidic Protein/blood , Glial Fibrillary Acidic Protein/immunology , Glial Fibrillary Acidic Protein/cerebrospinal fluid , Hashimoto Disease/diagnosis , Hashimoto Disease/blood , Magnetic Resonance Imaging
20.
Neurobiol Aging ; 140: 102-115, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38763075

ABSTRACT

Astrocyte heterogeneity and its relation to aging in the normal human brain remain poorly understood. We here analyzed astrocytes in gray and white matter brain tissues obtained from donors ranging in age between the neonatal period to over 100 years. We show that astrocytes are differently distributed with higher density in the white matter. This regional difference in cellular density becomes less prominent with age. Additionally, we confirm the presence of morphologically distinct astrocytes, with gray matter astrocytes being morphologically more complex. Notably, gray matter astrocytes morphologically change with age, while white matter astrocytes remain relatively consistent in morphology. Using regional mass spectrometry-based proteomics, we did, however, identify astrocyte specific proteins with regional differences in abundance, reflecting variation in cellular density or expression level. Importantly, the expression of some astrocyte specific proteins region-dependently decreases with age. Taken together, we provide insights into region- and age-related differences in astrocytes in the human brain.


Subject(s)
Aging , Astrocytes , Gray Matter , White Matter , Humans , Astrocytes/pathology , Astrocytes/metabolism , Aging/pathology , Aging/physiology , Gray Matter/pathology , Gray Matter/cytology , Adult , Aged , White Matter/pathology , White Matter/cytology , Young Adult , Middle Aged , Aged, 80 and over , Child , Infant , Child, Preschool , Adolescent , Infant, Newborn , Brain/cytology , Brain/pathology , Brain/metabolism , Proteomics , Male , Female , Cell Count
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